The present invention relates to condensation polymers for antimicrobial applications, and more specifically, to cationic forms of polycondensation polymers for topical antibacterial use.
Antimicrobial agents are commonly used in personal care products to inhibit microbial growth and infections therefrom, and product decomposition. Most antimicrobial agents used in these products are small molecules, including anilides (e.g., triclocarban), bis-phenols (e.g., triclosan), biguanides (e.g., chlorhexidine) and quaternary ammonium compounds (e.g., cetylpyridium chloride and cetrimide). Among them, triclosan is one of the most extensively used compounds. Triclosan is present in more than 50% of consumer products including soap, deodorant, toothpaste, mouth wash, cosmetics (e.g., Garden Botanika® Powder Foundation, Mavala Lip Base, Jason Natural Cosmetics and Movate® Skin Litening Cream HQ), cleaning supplies, kitchen utensils, children's toys, bedding, socks, shoes and trash bags. It is effective against Gram-positive bacteria, while it has little activity against P. aeruginosa (Gram-negative bacteria) and molds. At high concentrations, it is biocidal with multiple cytoplasmic and membrane targets. However, at low concentrations, it is bacteriostatic by inhibiting fatty acid synthesis. On the other hand, triclosan has cumulative and persistent effects on the skin. It was found in human breast milk and urine samples. At minimal concentrations of triclosan (<μg/L) and chlorine (<mg/L), common household tap water levels, triclosan can degrade to form toxic derivatives, 2,4-dichlorophenol and 2,4,6-trichlorophenol. Moreover, in sunlight and wastewater chlorine treatment, it also forms highly toxic carcinogenic dioxin-like compounds. After use, it is discharged into water. Triclosan was found in 85 out of 139 streams and rivers in 30 states in the US, and is toxic to aquatic species. It is persistent in the environment, and was detected in sediments in a Swiss lake as far back as the 1960s. Therefore, the use of triclosan in consumer products will be banned in Europe and in the United States within 2 years.
Many strains of bacteria spores (e.g., Clostridium species), Gram-positive bacteria (e.g., mycobacteria) and Gram-negative bacteria (e.g., Pseudomonas aeruginosa (P. aeruginosa)) have intrinsic resistance to the antimicrobial agents listed above. Moreover, these antimicrobial agents are not effective against biofilms. For example, Serratia marcescens (S. marcescens) and Burkholderia cepacia (B. cepacia) biofilms were found in disinfectant chlorhexidine solution, P. aeruginosa biofilm in iodophor antiseptics and on the interior surface of polyvinyl chloride pipes used in the production of providone-iodine antiseptics. Overuse of these antimicrobial agents has led to drug resistance in microbes. Major concerns include cross-resistance and co-resistance with clinically used antimicrobial agents, which may present a potential public health risk.
Most small molecule antimicrobial agents do not physically damage the cell wall, but rather penetrate the cell wall and act on specific intracellular targets. Consequently, bacterial morphology is preserved, allowing bacteria to easily develop resistance. Antimicrobial peptides (AMPs) have been explored as an alternative. AMPs (e.g., magainins, alamethicin, protegrins and defensins) do not have a specific target in microbes. They interact with microbial membranes based on electrostatic interaction, inducing damage to the microbial membranes by forming pores in the membranes. The physical nature of this action prevents microbes from developing resistance to AMPs. Although efforts have been made to design synthetic peptides with various structures over the last two decades, high manufacturing cost has limited their application in personal care products.
A number of cationic polymers that mimic the facially amphiphilic structure and antimicrobial functionalities of peptides have been proposed that can be more easily prepared at low cost and on large scale compared to peptides. For example, antimicrobial polynorbornene and polyacrylate derivatives, and pyridinium copolymers were synthesized either from amphiphilic monomers (homopolymers) or from cationic (hydrophilic) monomer and hydrophobic comonomer (random copolymers). However, most antimicrobial polymers reported in the literature are non-biodegradable and/or require several steps of synthesis. With the high volume of poorly degradable single-use consumer products already destined for landfills, the problem would be exacerbated by the addition of non-biodegradable antimicrobial materials that destroy bacteria and fungi responsible for slow landfill degradation.
A number of biodegradable cationic polycarbonates having high potency towards pathogenic microbes and low toxicity. These cationic polycarbonates degrade in aqueous solution especially in an alkaline environment which is often found in consumer care products. On the other hand, the synthesis of polycarbonates requires several steps like monomer synthesis, ring-opening polymerization and post-quaternization, which can translate into high consumer prices.
Currently, biodegradable, safe and cost-effective antimicrobial agents are needed for use in personal care products that can kill multidrug-resistant bacteria and fungi, remove biofilms, and prevent drug resistance.